2'-(tert-butyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one hydrochloride | 1197815-65-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2'-(tert-butyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one hydrochloride
• 英文别名: 2'-tert-Butyl-2'H-spiro[piperidine-4,5'-pyrano-[3,2-c]pyrazol]-7'(6'H)-one hydrochloride；2-tert-butylspiro[6H-pyrano[3,2-c]pyrazole-5,4'-piperidine]-7-one;hydrochloride
• CAS: 1197815-65-8
• 化学式: C₁₄H₂₁N₃O₂*ClH
• 分子量: 299.801
• InChiKey: LVESAGWWWIILLK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.15
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  56.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2'-(tert-butyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one hydrochloride 、 吲唑-5-甲酸盐酸盐 在 N-甲基吗啉 、 2-氯-4,6-二甲氧基-1,3,5-三嗪 作用下， 反应 2.5h， 以89%的产率得到2′-(tert-butyl)-1-(1H-indazole-5-carbonyl)-2′H-spiro-[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one
  参考文献：
  名称：

  Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase

  摘要：

  This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

  DOI：

  10.1021/jm201503u
• 作为产物：
  描述：

  2'-(叔丁基)-7'-氧代-6',7'-二氢-2'H-螺[哌啶-4,5'-吡喃并[3,2-C]吡唑]-1-甲酸 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 4.0h， 以100%的产率得到2'-(tert-butyl)-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one hydrochloride
  参考文献：
  名称：

  Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase

  摘要：

  This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

  DOI：

  10.1021/jm201503u

文献信息

• Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase Inhibitors through Liver Targeting
  作者：Kim Huard、Aaron C. Smith、Gregg Cappon、Robert L. Dow、David J. Edmonds、Ayman El-Kattan、William P. Esler、Dilinie P. Fernando、David A. Griffith、Amit S. Kalgutkar、Trenton T. Ross、Scott W. Bagley、David Beebe、Yi-An Bi、Shawn Cabral、Collin Crowley、Shawn D. Doran、Matthew S. Dowling、Spiros Liras、Vincent Mascitti、Mark Niosi、Jeffrey A. Pfefferkorn、Jana Polivkova、Cathy Préville、David A. Price、Andre Shavnya、Norimitsu Shirai、Andrew H. Smith、James R. Southers、David A. Tess、Benjamin A. Thuma、Manthena V. Varma、Xiaojing Yang

  DOI：10.1021/acs.jmedchem.0c00640

  日期：2020.10.8

  and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable

  临床前和临床数据表明，乙酰辅酶A羧化酶（ACC）抑制剂具有重新平衡紊乱的脂质代谢的潜力，从而改善了非酒精性脂肪性肝炎（NASH）。与这些观察结果一致，使用我们的ACC抑制剂PF-05175157进行的首次人类临床试验导致从头脂肪形成（DNL）的有效减少，尽管伴随血小板数量的减少，这归因于脂肪酸在体内的合成受到抑制骨髓。在本文中，我们描述了具有有机阴离子转运多肽（OATP）底物特性的基于羧酸的ACC抑制剂的设计，合成和评估，该抑制剂可促进化合物相对于外围在治疗作用部位（肝脏）的选择性分布。12），其选择性抑制动物肝脏DNL，同时在非人灵长类动物模型中显示出相当大的安全性，可防止血小板减少。
• Pyrazolospiroketone Acetyl-Coa Carboxylase Inhibitors
  申请人：Freeman-Cook Kevin Daniel

  公开号：US20110009443A1

  公开（公告）日：2011-01-13

  The invention provides compounds of Formula (1) or a pharmaceutically acceptable salt of said compound, wherein R 1 , R 2 , and R 3 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating mammals suffering from the condition of being overweight.

  本发明提供了式（1）的化合物或其药学上可接受的盐，其中R1、R2和R3如本文所述；其制备的药物组合物；以及用于治疗患有超重症的哺乳动物的用途。
• Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase
  作者：Kevin D. Freeman-Cook、Paul Amor、Scott Bader、Leanne M. Buzon、Steven B. Coffey、Jeffrey W. Corbett、Kenneth J. Dirico、Shawn D. Doran、Richard L. Elliott、William Esler、Angel Guzman-Perez、Kevin E. Henegar、Janet A. Houser、Christopher S. Jones、Chris Limberakis、Katherine Loomis、Kirk McPherson、Sharad Murdande、Kendra L. Nelson、Dennis Phillion、Betsy S. Pierce、Wei Song、Eliot Sugarman、Susan Tapley、Meihua Tu、Zhengrong Zhao

  DOI：10.1021/jm201503u

  日期：2012.1.26

  This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.